The metallothioneins provide a useful model to study how eukaryotic genes are regulated and how the gene products allow cellular adaptation and homeostasis. A mouse nuclear factor that binds to the metal control sequences of the mouse metallothionein-I gene has been identified and is being purified. Developmental regulation of the mammalian genes is being studied by transfection and transgenic animal experiments. Using yeast as a simple model system, trans-acting genes involved in metallothionein gene expression are being identified and cloned. Structure function studies of yeast metallothionein suggest the presence of preferred nucleation sites for the cooperative folding of this protein.